1. Field of the Invention
The invention relates to development of cancer drug, especially relates to the development of novel thiochromeno[2,3-c]quinolin-12-one derivatives, preparation method and application thereof.
2. Description of the Prior Art
Telomerase is the enzyme that synthesizes telomeric DNA, the terminal DNA at chromosome ends which, together with telomere-binding proteins, confers stability to chromosomes. In most of organism, the replication and maintenance of the length of telomere has to rely on telomerase. The telomerase is composed of RNA and protein subunits. At present, part of important telomerase subunits had been identified. The composition of human telomerase comprising: human telomerase reverse transcriptase (hTERT) having reverse transciptase activity, human telomerase RNA component used as a template, and some telomere-binding proteins such as human telomerase-associated protein, p23, hsp90, hsp40, hsp70 and the like.
Many research studies had indicated that the activity of human telomerase can only be detected in cells having high proliferation ability, for example, germ cells, hemopoietic cells, part of stem cells, most of immortalized cells and most of tumor cells. In the somatic cell, the telomere will be shorten gradually as the number of cell division increased, which may be considered as the mitotic clock for counting the number of cell division. When a telomere is shortened to a certain extent, cell will stop division and entering aging stage, stay at this stage for a period of time, and then goes to death. This period of time is called mortality stage 1 (M1 stage). When a tumor suppressor gene such as p53 or Rb is mutated within M1 stage, the cell might escape from aging stage and keeps on cell division in this period of time which is called mortality stage 2 (M2 stage). If a cell lacks of telomerase activity during this period, the length of a telomere will be reduced still, the telomere will not be able to protect the terminal end of the chromosome, and this might result into the instability of the chromosome, as well as the cell can not transfer genetic information completely and enters apoptosis in the end. Therefore, M2 stage is also called a crisis stage. Most of cells will die in M2 stage, except small part of cells with telomerase activity will survive. This small part of cells will continue to divide without limitation and become an immortalized cell (or a cancer cell).
In view of the foregoing, it is thought generally that the activation of telomerase can maintain the length of a telomere so as to prevent a cell from entering the ageing stage; or the inhibition of telomerase activity can be used to limit the division of a cancer cell. Both thought may become the key factors in the development of a cell toward immortalization or cancerization. In summary, using the telomerase inhibitors to treat the cancer have been considered as a novel cancer-specific therapy, as most tumor cells have high expression of telomerase, whereas most normal somatic cells express low or undetectable levels of telomerase and is therefore an attractive target for the design of anticancer agents.
Cancers arise from abnormal proliferation of DNA. Therefore, selectively destroy the DNA of cancer cells without damaging the DNA of normal cells is highly desired. However, it is difficult to differentiate the DNAs between normal cells and cancer cells. Consequently, specific ‘targeted therapy’ was developed following identification of the differences between normal cells and cancer cells, and when combined with other chemotherapies or radiation therapies, targeted therapy can significantly reduce side effects and provide better treatment outcomes. Thus, targeted therapy currently is a popular field in studying cancer treatments. Because topoisomerases have been found to play an indispensible role in DNA replication, they have become the objects of targeted therapy for anticancer treatments. The anticancer drug camptothecin discovered by M. E. Wall and M. C. Wani in 1966 through systematic screening of natural substances is an inhibitor for type I topoisomerases.
Unfortunately, camptothecin has numerous disadvantages and thus cannot be used for clinical treatment. For example, the lactone ring can be easily hydrolyzed to hydroxycarboxylate in vivo at the normal pH and then binds to serum albumin and lose its effect of inhibiting the function of type I topoisomerases. In addition, the structure of the tricomplex of camptothecin-Top I-DNA is not stable because the complex is not maintained by covalent bonds and water solubility of camptothecin is poor which causes lower bioavailability. The p-glycoprotein (MDR1, ABCB1) efflux transporter proteins in the cell membrane transported the drugs out of the cells and more important is that some tumor cells have slowly developed resistance and adverse drug side effects against camptothecin. As a result, a number of water-soluble semi-synthetic drugs were developed even after commercialization of camptothecin such as Topotecan (HYCAMTIN®) which is used for treating ovarian cancer and Irinotecan (CAMPTO®) which is used for treating colon cancer and both have issues when used for clinical treatment.
Hence, based on the importance of topoisomerase inhibitors in development of anticancer drugs, the inventor of this application developed a series of novel thiochromeno[2,3-c]quinolin-12-one derivatives and disclosed the preparation methods as well as relevant applications herein after a number of innovative improvements.